There has been a continuing need for effective chemotherapeutic agents and drugs embodying chemotherapeutic agents which are effective in inhibiting the growth of cancer. One type of chemotherapeutic agent which has demonstrated cancer inhibiting qualities is the folic acid antagonist (antifolate). Antifolates are thought to be effective chemotherapeutic agents because various coenzyme forms of folic acid are essential for biosynthesis of the thymine and purine precursors of DNA. Thus, suppressing such coenzyme forms of folic acid is considered as suppressing materials essential for cell division and cellular proliferation. Typically, antifolate drugs currently being used as chemotherapeutic agents act to interfere with microbial folic acid biosynthesis or act by inhibition of bacterial, plasmodial or mammalian dihydrofolate reductases in the animal body. A problem persists, however, with use of current antifolates in that they typically display poor penetration into solid tumors, particularly of the brain thus manifesting low efficiency. Current antifolates also display severe toxicity to rapidly proliferating normal tissues thus presenting a major limitation to their use in the treatment of malignancies in warm blooded animals.
Folates occur in nature predominantly as poly-gamma-glutamates containing 3-7 or even more glutamate residues. The occurrence of folate polyglutamates is universal. These metabolic forms have been identified in many species of animals as well as in all human tisues, blood cells and lymphocytes. The metabolically functional forms of folates are polyglutamylated tetrahydrofolates, serving as cofactors for a variety of enzyme catalyzed reactions inside the cell. The enzyme responsible for the formation of poly-gamma-glutamates is folylpolyglutamate synthetase. Its vital function is evidenced by the inability of mutant mammalian cells lacking this enzyme to survive in the absence of thymidine, glycine and adenine, which are the products of folate requiring metabolic pathways.
Though the essential role of folate polyglutamylation is not fully understood, it has been found that many folate requiring enzymes have higher affinity to their polyglutamylated cofactors than to the corresponding monoglutamates. Long chain polyglutamyl derivatives of methotrexate (MTX), an effective antiproliferative agent, enhance the intracellular retention of the drug and since "free" exchangeable MTX, in excess of that bound to dihydrofolate reductase, is required for complete inhibition of the enzyme, polyglutamylation helps to maintain the needed intracellular drug level. In addition to dihydrofolate reductase, the primary target of MTX, polyglutamate derivatives of the drug are also inhibitory to other essential folate requiring enzymes. Thus, compounds which are able to protect the polyglutamates of MTX from metabolic degradation to shorter chain derivatives, would have the indirect effect of inhibiting cancer by enhancing (potentiating) the activity of MTX.
In high dose MTX cancer treatment programs, wherein the patient is exposed to severe systemic toxicity risk with dosages of MTX approaching or exceeding the lethal level, Leucovorin is typically used as a "rescue" agent to rescue normal cells and thereby prevent toxicity. Thus, compounds which have a dual effect in that they enhance the activity of MTX in the cancer tumor while at the same time enhancing the effect of Leucovorin in protecting normal cells would be of significant pharmacological value.
Methotrexate and other antifolates have also been identified as active agents in the treatment of psoriasis but MTX is of such severe systemic toxicity that treatment to attain enough MTX at the sites of the psoriasis usually involves a toxic risk to the patient. Again, compounds which enhance the activity of MTX would have an indirect effect, being to inhibit psoriasis.
Methotrexate and other antifolates are additionally known as effective immunosuppressive agents thus having utility in preventing graft-versus-host reaction that result from tissue transplants, and utility in the management of dermatomyositis, arthritis, and other inflammatory diseases. As use of methotrexate and other antifolates as immunosupressive agents involves a systemic toxicity risk to the patient, compounds which enhance the activity of MTX and/or other antifolates would have a beneficial effect in such applications.
There has also been a continuing demand for new complexing agents which are capable of complexing with metal cations in such manner as to foster removal of such cations from various solutions. New agents are always in commercial demand because of the many different process parameters and formulations in which they may be used and the variation in characteristics that may be imposed upon such processes or formulations by the complexing agent.
The ability to complex pharmacologically active metals such as gold, copper and the like provides a further activity dimension to such compounds. Gold, particularly in the form of gold sodium thiomalate, is a drug of choice in the treatment of rhumatoid arthritis. Gold complex compounds which can provide the active gold metal together in a complex structure, which structure might be used for combination therapy, are thus pharmacologically desirable.
An object of this invention is to provide new compounds which selectively inhibit gamma-glutamyl hydrolases.
Another object of this invention is to provide new compounds useful as intermediates for the production of compounds which inhibit gamma-glutamate hydrolases.
A still further object is to provide new compounds which are precursors (prodrugs) for the in vivo conversion to compounds which inhibit gamma-glutamyl hydrolases.
A further object is to provide new compounds which enhance the activity of methotrexate and other antifolates.
An additional object of this invention is to provide new compounds useful as antidotes of carboxypeptidase G.
These and other objects of the invention will become apparent from the following description of the invention.